Stereochemistry in inactivation of carboxypeptidase A. Structural analysis of the inactivated carboxypeptidase A by an enantiomeric pair of 2-benzyl-3,4-epoxybutanoic acids

Seong Eon Ryu, Hee Jeong Choi, Dong H. Kim

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32 Citations (Scopus)

Abstract

The X-ray crystal structure of inactivated carboxypeptidase A by (2R,3S)-2-benzyl-3,4-epoxybutanoic acid, a pseudomechanism-based inactivator, was determined to show that the carboxylate of Glu-270 at the active site of the enzyme is covalently modified: the inhibitor is tethered to the carboxylate forming an ester linkage which is brought about by the attack of the carboxylate on the oxirane ring of the inhibitor. Examination of the crystal structure in comparison with that inactivated by its enantiomer, (2S,3R)-2-benzyl-3,4-epoxybutanoic acid, shows that the two inhibitors are bound covalently to the enzyme in a symmetrical fashion. An explanation for the lack of inactivating activity found previously with (2R,3R)- as well as (2S,3S)-2-benzyl-3,4-epoxybutanoic acids was offered.

Original languageEnglish
Pages (from-to)38-41
Number of pages4
JournalJournal of the American Chemical Society
Volume119
Issue number1
DOIs
StatePublished - 1997 Jan 8

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Carboxypeptidases A
Stereochemistry
Structural analysis
Acids
Enzymes
Crystal structure
Ethylene Oxide
Enantiomers
Catalytic Domain
Esters
X-Rays
X rays

Cite this

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title = "Stereochemistry in inactivation of carboxypeptidase A. Structural analysis of the inactivated carboxypeptidase A by an enantiomeric pair of 2-benzyl-3,4-epoxybutanoic acids",
abstract = "The X-ray crystal structure of inactivated carboxypeptidase A by (2R,3S)-2-benzyl-3,4-epoxybutanoic acid, a pseudomechanism-based inactivator, was determined to show that the carboxylate of Glu-270 at the active site of the enzyme is covalently modified: the inhibitor is tethered to the carboxylate forming an ester linkage which is brought about by the attack of the carboxylate on the oxirane ring of the inhibitor. Examination of the crystal structure in comparison with that inactivated by its enantiomer, (2S,3R)-2-benzyl-3,4-epoxybutanoic acid, shows that the two inhibitors are bound covalently to the enzyme in a symmetrical fashion. An explanation for the lack of inactivating activity found previously with (2R,3R)- as well as (2S,3S)-2-benzyl-3,4-epoxybutanoic acids was offered.",
author = "Ryu, {Seong Eon} and Choi, {Hee Jeong} and Kim, {Dong H.}",
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T1 - Stereochemistry in inactivation of carboxypeptidase A. Structural analysis of the inactivated carboxypeptidase A by an enantiomeric pair of 2-benzyl-3,4-epoxybutanoic acids

AU - Ryu, Seong Eon

AU - Choi, Hee Jeong

AU - Kim, Dong H.

PY - 1997/1/8

Y1 - 1997/1/8

N2 - The X-ray crystal structure of inactivated carboxypeptidase A by (2R,3S)-2-benzyl-3,4-epoxybutanoic acid, a pseudomechanism-based inactivator, was determined to show that the carboxylate of Glu-270 at the active site of the enzyme is covalently modified: the inhibitor is tethered to the carboxylate forming an ester linkage which is brought about by the attack of the carboxylate on the oxirane ring of the inhibitor. Examination of the crystal structure in comparison with that inactivated by its enantiomer, (2S,3R)-2-benzyl-3,4-epoxybutanoic acid, shows that the two inhibitors are bound covalently to the enzyme in a symmetrical fashion. An explanation for the lack of inactivating activity found previously with (2R,3R)- as well as (2S,3S)-2-benzyl-3,4-epoxybutanoic acids was offered.

AB - The X-ray crystal structure of inactivated carboxypeptidase A by (2R,3S)-2-benzyl-3,4-epoxybutanoic acid, a pseudomechanism-based inactivator, was determined to show that the carboxylate of Glu-270 at the active site of the enzyme is covalently modified: the inhibitor is tethered to the carboxylate forming an ester linkage which is brought about by the attack of the carboxylate on the oxirane ring of the inhibitor. Examination of the crystal structure in comparison with that inactivated by its enantiomer, (2S,3R)-2-benzyl-3,4-epoxybutanoic acid, shows that the two inhibitors are bound covalently to the enzyme in a symmetrical fashion. An explanation for the lack of inactivating activity found previously with (2R,3R)- as well as (2S,3S)-2-benzyl-3,4-epoxybutanoic acids was offered.

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